Abstract Alzheimer's disease (AD) is a major, growing global public health problem. This is a daunting scientific challenge and solutions will come only from innovative research. We have brought together a unique interdisciplinary team of investigators with the goal of bridging the divide between state-of-the-art technologies and translational applications. To monitor AD disease progression or response to treatment, cerebrospinal fluid (CSF) represents the preferred fluid to reflect brain pathophysiology. The brain interstitial fluid is in direct contact with the CSF by unrestricted bidirectional flow of proteins and the CSF is protected from the peripheral system because of the ? restricted transportation of molecules and proteins by the blood-brain barrier. Known CSF biomarkers have been demonstrated to reflect the three main pathological changes that occur in the AD brain -- amyloid- deposition, neurofibrillary degeneration, and neuronal injury. Therefore, analysis of molecules and particles in CSF holds the greatest potential to improve our diagnosis and characterization of neurodegenerative diseases in vivo. We propose to enable precision medicine for AD by developing a cooperative research program that will unite a unique research team with the specific goal of vastly improving the molecular characterization of CSF as predictors of cognitive decline and AD pathophysiology. The efforts of this program will complement existing efforts to accelerate the identification and validation of clinically relevant therapeutic targets. We will work in parallel with programs like Accelerating Medicines Partnership (AMP) and the AD Centers Program, to provide unique diagnostic capabilities in support of the process of bringing new medicines to patients. Our U19 research program will consist of four projects and four cores that are synergistic to our mission. Moreover, our research team is uniquely suited to the development, validation and translational application of new biomolecular assays to reflect AD pathophysiology. This U19 will harness the collective expertise of multiple fields, combined with the financial resources sufficient to extend and apply next generation proteomics technologies to clinical specimens that have been extensively annotated with longitudinal, consensus clinical diagnostic and neuropsychological test data. We will create new assays with the goal of deployment to the clinical lab. We will create unique and sustainable reagents that will facilitate dissemination and deployment of these methods worldwide. Our program will expand existing infrastructure, developed by our labs, for sharing and disseminating these data and protocols. The application of new technologies, development of novel reagents, creation of new clinical assays, and dissemination of data and protocols will accelerate neuroscience in a way not feasible under traditional NIH mechanisms.